Associations of Severity of Dry Eye Symptoms and Signs with the Quality of Life in the Dry Eye Assessment and Management (DREAM) Study

Purpose: To assess associations of dry eye disease (DED) severity of symptoms and signs with the quality of life in patients with moderate-to-severe DED. Methods: At baseline, 6 and 12 months, participants (N=535) were assessed for DED symptoms using Ocular Surface Disease Index (OSDI) and signs using conjunctival staining, corneal staining, tear breakup time (TBUT), Schirmer’s testing, meibomian gland dysfunction, and tear osmolarity. Quality of life was evaluated using the Short Form Health Survey (SF-36), consisting of Physical Component Summary (PCS) and Mental Component Summary (MCS). Spearman correlation coefficients (rho) were used to evaluate correlations between the severity of DED and SF-36. Results: At baseline, Worse DED symptoms indicated by higher OSDI total score were correlated with worse PCS (rho=−0.13, P=0.002) and MCS (rho=−0.09, P=0.03) of SF-36. The worse vision-related function was correlated with a worse PCS score (rho=−0.18, P<0.0001), and worse ocular symptoms were correlated with a worse MCS score (rho=−0.15, P<0.001). More severe DED signs including corneal staining (rho=−0.22, P<0.001), Schirmer test (rho=0.11, P=0.01), TBUT (rho=0.14, P<0.001), and tear osmolarity (rho=−0.12, P=0.02) were correlated with worse PCS score but were not correlated with MCS score (P≥0.39). ln longitudinal analysis, only worsening of ocular symptoms was significantly correlated with worsening of MCS score (rho=−0.09, P=0.04). Conclusion: In patients with moderate-to-severe DED, there were significant yet weak correlations between dry eye severity of symptoms/signs and physical or mental components of SF-36. Healthcare professionals should offer DED symptom relief and support for the emotional and practical challenges in their daily lives.


INTRODUCTION
Dry eye disease (DED), a multifactorial ocular disorder, affects approximately 9-30% of adults in the United States, with higher rates observed among women and increasing age groups. 1 Dry eye disease is characterized by inadequate tear production or excessive evaporation, leading to ocular discomfort and potential damage to the ocular surface. 2 Dry eye manifests through a range of distressing symptoms that can signi cantly impact an individual's daily life.Numerous studies have established the profound impact of DED on the quality of life of DED patients.Research has revealed that DED has a direct impact on many aspects of quality of life, including physical health, psychological well-being, and level of independence. 3tients with DED commonly experience sensations of ocular dryness, grittiness, burning, itching, or foreign body sensation.Additionally, they may experience frequent tearing, uctuating visual acuity, and sensitivity to light.These symptoms may worsen during prolonged periods of reading, computer usage, or exposure to environmental factors such as wind, smoke, or dry air. 3Furthermore, inadequate tear production and poor tear quality associated with DED can cause blurred or uctuating vision and may result in glare or haloes around lights, particularly at night. 4 Dry eye disease also signi cantly reduces all components of sleep quality even after adjusting for confounders. 4All these contribute to the reduced quality of life in patients with DED.
Although many studies have elucidated the substantial effect of DED on quality of life, few large studies have evaluated the association between the severity of DED and quality of life.To evaluate associations between DED severity and quality of life among patients with DED, we performed a secondary analysis of rich data from the Dry Eye Assessment and Management (DREAM) study, 5 a large-scale, multicenter, placebo-controlled clinical trial of a well-characterized cohort of DED patients.

Participants
The DREAM Study (ClinicalTrials.govidenti er, NCT02128763, registered on April 28, 2014), funded by the National Eye Institute, enrolled 535 adult patients with DED from 27 clinical centers in the United States between October 2014 and July 2016. 5The patients were randomized in a 2:1 ratio, to the active group receiving an oral omega-3 fatty acid supplement (2000 mg eicosapentaenoic acid [EPA] and 1000 mg docosahexaenoic acid [DHA] per day), and the placebo group receiving re ned olive oil.The study followed the principles of the Declaration of Helsinki.Institutional review board approval was obtained from each center, and written informed consent was obtained from all participants.
The DREAM Study aimed to include a diverse range of patients with symptomatic moderate-to-severe DED.Major eligibility criteria included being 18 years or older, experiencing dry eye-related ocular symptoms for at least 6 months prior to the screening visit, using or intending to use arti cial tears at least twice daily for the 2 weeks preceding the screening visit, and having an Ocular Surface Disease Index (OSDI) score between 25 and 80 at the screening visit and 21 to 80 at the baseline visit.Additionally, patients had to meet at least two of the following four criteria for dry eye signs in the same eye at both the screening and baseline visits: (1) conjunctival lissamine green staining score of 1 or more (on a scale of 0-6), (2) corneal uorescein staining score of 4 or more (on a scale of 0-15), (3) tear lm breakup time (TBUT) of 7 seconds or fewer, and (4) anesthetized Schirmer test score of 1 to 7 mm per 5 minutes.Further details on the inclusion and exclusion criteria can be found in the DREAM Study protocol. 5

Evaluation of DED Symptoms and Signs
The severity of DED symptoms was assessed using the OSDI, which includes three subscales consisting of vision-related function, ocular symptoms, and environmental triggers.The tota score and each subscale score of OSDI range from 0 to 100 with higher scores indicating more severe symptoms of DED.
Assessment of DED signs in each eye followed a standardized protocol.Corneal uorescein staining was assessed using the National Eye Institute scale whereby 5 areas of the cornea are graded 0 to 3, for a total possible score of 0 to 15 per eye, with a higher score indicating greater abnormality.Conjunctival lissamine green staining was assessed on a scale of 0 to 3 in the nasal and temporal areas for a total possible score of 0 to 6 per eye, with a higher score indicating a greater abnormality.To measure TBUT, a solution 5 mL of 2% uorescein solution was administered into the lower cul-de-sac of the eye.After a 30-second waiting period, the cornea was observed using a slit lamp with broad beam cobalt blue illumination and a yellow barrier lter.The patient was instructed to blink, and the TBUT was measured to be the time it took for the rst break in the tear lm to appear.TBUT was measured three times for each eye, and the average value was calculated for analysis.Lower scores of TBUT indicated a higher level of abnormality.The Schirmer test was conducted to evaluate tear production, with lower scores indicating greater abnormality.For the Schirmer test, topical anesthesia was rst applied.After approximately 5 minutes, test strips were placed in the temporal one-third of the lower conjunctival sac of each eye, and the patient was instructed to close both eyes.Following a 5-minute period, the strips were carefully removed, and the length of wetting on the strips was recorded in millimeters.Tear osmolarity was measured for the concentration of solutes in the tear lm on a scale of 275 to 400 mOsm/l, and higher scores indicated greater abnormality.Clinicians assessed meibomian gland dysfunction (MGD) based on the degree of plugging and secretion observed at the lower eyelid margin, each on a scale of 0 to 3. Scores for MGD were calculated as the total score of plugging and secretion, with total scores ranging from 0 to 6 and higher scores indicating more severe dysfunction.These DED symptoms and signs were measured at baseline, 6, and 12 months.

Evaluation of Quality of Life
The quality of life was measured by the Short Form Health Survey (SF-36) version 2.0, consisting of generic, coherent, and easily administered quality-of-life measures. 6The 36-item questionnaire was divided into two components: the Physical Component Summary (PCS) and Mental Component Summary (MCS), with 8 subscales (physical functioning, role limitations due to physical health, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems, and mental health).The scores of PCS and MCS ranged from 0-100, with higher scores indicating a higher level of well-being. 6The SF-36 questionnaire was administered to patients at baseline, 6, and 12 months.

Statistical Analysis
Data from both treatment groups were combined for all statistical analysis because the results of the DREAM study showed that there were no signi cant differences between participants randomized to n-3 fatty acids or placebo in any primary outcome and secondary outcomes of DED symptoms and signs, and SF-36. 7e to the non-normality of the DED symptoms and signs, the Spearman correlation coe cient (rho) was used to assess the association between the dry eye symptoms, signs, and SF-36 at baseline.The dry eye symptoms were evaluated using the OSDI overall total score and 3 subscale scores (vision-related function, ocular symptoms, and environmental triggers).Dry eye sign in the worse eye (speci c to each sign) was analyzed for conjunctival staining score, corneal staining score, Schirmer test score, TBUT, tear osmolarity, and MGD.The SF-36 scores were analyzed for the physical component score and the mental component score separately following the SF-36 user's manual. 8Furthermore, partial Spearman correlation coe cients adjusted by randomized treatment group were calculated for evaluating the associations between changes in dry eye symptoms and signs, and change in SF-36 from baseline at 12 months.The 95% con dence intervals (95% CI) for Spearman correlation coe cients and associated pvalues were calculated using bootstrap. 9e strength of association was determined based on Spearman correlation coe cients 10 : 0 to 0.19 = very weak, 0.20 to 0.39 = weak, 0.40 to 0.59 = moderate, 0.60 to 0.79 = strong, and 0.80 to 0.99 = very strong.All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC) and twosided P < 0.05 were considered statistically signi cant.

Baseline Characteristics
The baseline characteristics of the 535 study participants with moderate-to-severe DED are summarized in Table 1.The mean ± standard deviation (SD) of age was 58 ± 13.2 years, with most participants comprised of women (81%) and White race (74%).The Hispanic or Latino ethnic group consisted of 13% of the participants, 52 (9.7%) had Sjögren Syndrome based on the 2012 American College of Rheumatology classi cation criteria.Baseline correlations between dry eye signs and SF-36 are summarized in Table 3. Worse SF-36 physical component score was signi cantly associated with more severe signs in terms of corneal staining score (rho=-0.22,P < 0.001), Schirmer test score (rho = 0.11, P = 0.01), tear break-up time (rho = 0.14, P < 0.001), and tear osmolarity (rho=-0.12,P = 0.02).However, there was no signi cant correlations between the SF-36 mental component score and dry eye signs (p ≥ 0.39).* The change (Month 12 -baseline) from the eye with worse sign at baseline was used for analysis.

DISCUSSION
This study evaluated associations between the severity of DED symptoms and signs and the quality of life in a large, demographically diverse cohort of patients with moderate-to-severe DED.We found a weak yet statistically signi cant correlation between the severity of DED symptoms and signs with both the physical and mental components of quality of life assessed by the generic SF-36.Dry eye symptoms as measured by OSDI are weakly correlated with both the physical component and mental component of SF-36 (absolute correlation coe cient ≤ 0.13).Similarly, the OSDI vision-related function subscale score is weakly correlated with the SF-36 physical component score (rho=-0.18)and the ocular symptoms subscale is weakly correlated with the SF-36 mental component score (rho=-0.15).However, there is no signi cant correlation between the subscale of environmental triggers and SF-36.These ndings are consistent with prior studies that found ocular discomfort scores were correlated moderately to strongly with OSDI, and with measures of activities of daily living.Speci cally, Sayegh et al found a signi cant correlation between OSDI scores and ocular discomfort (Spearman correlation coe cient, rho = 0.47-0.67)and with measures of activities of daily living (rho = 0.39-0.65). 11In another study, Dias et al. investigated the quality of life in patients with primary Sjögren's and, after matching with healthy controls by age and gender, found that SF-36 and World Health Organization Quality of Life Assessment (WHOQOL-BREF) values were lower in patients with primary Sjögren's (p < 0.001), except in the WHOQOL-BREF environment domain.They also found that those with pain and fatigue were signi cant predictors of poorer quality of life. 12 also found a signi cant yet weak correlation between four out of the six individual dry eye signs and the physical component score of the SF-36 at baseline.The number of signs ful lling the enrollment criteria at baseline was signi cantly associated with the physical component score of the SF-36.This implies that the cumulative burden of DED signs may have a signi cant in uence on the physical health of dry eye patients.
Prior studies have found an association between the presence of DED and mental health.Through metaanalysis, Wan et al reported a signi cantly higher prevalence and severity of depression and anxiety in DED patients than in controls. 13Mertzanis et al. found that all SF-36 subscales except mental health (Effect Size (ES) = 0.12) were lower in the Sjögren syndrome group than in the normal control group.Even the group with severe disease scored lower than the control group across all domains (ES range: -0.14 to -0.91) except role-emotional (ES = 0.13) and mental Health (ES = 0.23). 14Different from previous studies, our study evaluated associations between the severity of DED (in terms of symptoms and signs) and the mental component of SF-36.However, we only found a weak yet signi cant association between the OSDI ocular symptoms subscale and the SF-36 mental component score (rho=-0.15).Furthermore, we found the number of signs ful lling the enrollment criteria at baseline was not signi cantly associated with the mental component score of the SF-36.The con icting results suggest that further investigation into the association between mental health and DED is needed.
The impact of DED extends across a wide spectrum of individuals' quality of life beyond the visual component, and encompasses aspects of activities of daily living, social and physical functioning, and workplace productivity. 2Using data from a large therapeutic trial, Cornec et al identi ed the main determinants of health-related quality of life (HRQOL) impairments in patients with active primary Sjögren's syndrome, with one-third of the patients exhibiting low, moderate, and high systemic activity.They found that lower SF-36 scores indicated a marked HRQOL impairment in the population with active primary Sjögren's syndrome and were most strongly associated with patient-reported symptoms, and no associations between systemic activity level and HRQOL. 15Overall, compared to the weak associations we found, prior studies showed a stronger relationship between quality of life and dry eye symptoms and signs.This may be because previous studies included patients with mild DED or controls without DED, while our cohort only included those with moderate-to-severe DED.Nevertheless, our ndings add to the literature highlighting the importance of assessing the quality of life in patients with DED because it mirrors the impact of DED on their daily lives.
In the DREAM study, there were signi cant improvements between baseline and 12 months in DED symptoms and signs, but no signi cant change in SF-36.We did not nd any signi cant association between the change in dry eye symptoms and the change in SF-36 except for the weak yet signi cant correlation between ocular-related symptoms subscale and mental component score (rho=-0.09,P = 0.04).Similarly, we only nd a weak yet signi cant association between the change of the Schirmer test score and change of mental component score of SF-36 (rho = 0.09, P = 0.04).Although we found the change of osmolarity score was signi cantly correlated with the change of physical component score of SF-36 (rho = 0.16, P = 0.004), the correlation is in an unexpected direction (i.e., worsening in tear osmolarity was associated with improvement in physical component score).
While numerous investigations have previously investigated the signi cant in uence of DED on quality of life, the scarcity of large-scale studies focusing on the direct association between the severity of DED and quality of life underscores the strength of our study.By conducting a secondary analysis of rich data from the large meticulously characterized cohort of the multi-center DREAM study, we were able to provide a robust assessment of the impact of DED severity on quality of life.Furthermore, this extensive dataset encompasses a comprehensive standardized evaluation of dry eye symptoms and signs.One limitation of our study involves the use of questionnaires.The use of self-reported quality-of-life measures, such as the SF-36, relies on participants' subjective perceptions and may be in uenced by individual biases or social desirability, potentially impacting the validity of the results.Furthermore, the DREAM study only enrolled patients with moderate-to-severe DED without the inclusion of patients with mild DED, which may limit our capability to nd a stronger correlation.
In conclusion, our study has shed light on the multifaceted impact of dry eye disease severity on individuals' lives.The ndings have underscored the need for a comprehensive approach to DED management that addresses its physical, psychological, and socioeconomic dimensions.As we move forward, it is imperative that healthcare professionals consider the holistic well-being of DED patients, offering not only symptom relief but also support for the emotional and practical challenges they face in their daily lives.Additionally, further research is warranted to explore the complex interplay between DED and quality of life, particularly in the mental health component, allowing for the development of more targeted interventions and therapies to improve the lives of those affected by this condition.

Declarations
Funding Declaration: Supported by National Eye Institute Grants U10EY022879, U10EY022881, R21EY031338, P30-EY01583-26 and Research to Prevent Blindness (RPB) Unrestricted Grant.The funding organization had no role in the design or conduct of this research.
Human Ethics and Consent to Participate Declarations: The study followed principles of the Declaration of Helsinki.Institutional review board approval was obtained from each center, and written informed consent was obtained from all participants.
Consent to Publish: All authors consent to publish this manuscript

Table 1
Baseline characteristics of patients (n = 535) Sjögren syndrome was de ned by the 2012 American College of Rheumatology classi cation criteria for Sjögren Syndrome based on serology and ocular surface staining.Baseline correlations between OSDI and SF-36 are shown in Table2.More severe DED symptoms (as indicated by higher OSDI total score) were signi cantly associated with worse quality of life in both the *Sjögren syndrome was de ned by the 2012 American College of Rheumatology classi cation criteria for Sjögren Syndrome based on serology and ocular surface staining.**Without serology for antibody test for Sjögren syndrome.***Without serology for antibody test for Sjögren syndrome.At baseline, the mean ± SD for the total OSDI score was 44.4 ± 14.2.The mean ± SD for each OSDI subscale score was 37.8 ± 17.7 for vision-related function subscale, 46.6 ± 17.1 for ocular symptoms subscale, and 55.6 ± 24.5 for environmental triggers subscale.The mean ± SD for DED signs was 3.3 ± 1.5 for conjunctival staining score, 4.4 ± 3.1 for corneal staining score, 2.7 ± 1.4 for tear break-up time (sec), and 8.2 ± 6.3 for Schirmer's test (mm in 5 minutes), 308 ± 1.4 for tear osmolarity, and 1.7 7 ± 0.9 for MGD.To be enrolled in the study, the patients were required to have at least two of the four signs (conjunctival staining score, corneal staining score, tear break-up time, and Schirmer test score).There were 192 (35.9%) patients with two DED signs ful lling the criteria for enrollment, 203 (37.9%) patients with three signs, and 140 (26.2%)patients with four DED signs.The mean ± SD of the SF-36 score was 47.5 ± 9.7 for the physical component, and 52.3 ± 9.4 for the mental component.

Table 2
Correlations between dry eye symptoms and SF-36 at baseline (n = 535 patients)

Table 3
Correlations between dry eye signs and SF-36 at baseline (n = 535 patients) * The eye with worse sign was used in the calculation.Table4compares SF-36 scores across three groups of patients de ned by number of signs ful lling the enrollment criteria.The mean SF-36 physical component score signi cantly decreased with the increase of the number of signs ful lling the criteria, with mean Sf-36 scores of 49.** From analysis of variance.Associations for changes of dry eye symptoms and signs with changes of SF-36 baseline at 12 months Among 486 who completed the 12 months follow-up, the mean change from baseline at 12 months was signi cant for OSDI overall score (mean change=-11.6,P < 0.0001) and each subscale score (-10.4 for vision-related function score, -12.6 for ocular symptom score, -12.7 for environment triggers score, all P < 0.0001), the dry eye signs (-0.8 for conjunctival staining score, -1.1 for corneal staining score, 1.2 for Schirmer test score, 1.4 seconds for tear break-up time, -4.3 mOsm/l for tear osmolarity, and − 0.3 for MGD, all P < 0.001).However, there was no signi cant change in SF-36 physical component score (mean change = 0.1, P = 0.80), and mental component score (mean change=-0.3,P = 0.40).

Table 5
demonstrates the correlations between changes from baseline in dry eye symptoms and changes from baseline in SF-36 at 12 months.Only ocular symptoms subscale was signi cantly associated with SF-36 mental component score (rho=-0.09,P = 0.04).
*Partial correlation coe cients (rho) are calculated by adjusting for the treatment group.Table 6 demonstrates the correlations between changes from baseline in dry eye signs and changes from baseline in SF-36 at 12 months.Change of the Schirmer test score was signi cantly associated with the change of SF-36 mental component score (rho = 0.09, P = 0.04), and change of tear osmolarity score was signi cantly associated with change of SF-36 physical component score (rho = 0.16, P = 0.004).There was no other signi cant association between the change of DED signs and the change of SF-36.* Partial Spearman correlation coe cients (rho) are calculated by adjusting for the treatment group.